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IGFBP-3 Is a Direct Target of Transcriptional Regulation by Np63 in Squamous Epithelium

Departments of ¹ Biochemistry, ² Pathology, and ³ Biostatistics and ⁴ Center in Molecular Toxicology, the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Jennifer A. Pietenpol, 652 Preston Research Building, Vanderbilt University Medical Center, Nashville, TN 37232. Phone: 615-936-1512; Fax: 615-936-1790; E-mail: j.pietenpol{at}vanderbilt.edu.

Np63 is a nuclear transcription factor that maintains epithelial progenitor cell populations, is overexpressed in several epithelial cancers, and can negatively regulate apoptosis. However, the mechanisms by which Np63 promotes cell survival are unclear. Np63 has been reported to act as a transcriptional repressor, but specific target genes directly repressed by Np63 remain unidentified. Here, we present evidence that Np63 functions to negatively regulate the proapoptotic protein IGFBP-3. Disruption of p63 expression in squamous epithelial cells increases IGFBP-3 expression, whereas ectopic expression of Np63 down-regulates IGFBP-3. Np63 binds to sites in the IGFBP-3 gene in vivo and can modulate transcription through these sites. Furthermore, Np63 and IGFBP-3 expression patterns are inversely correlated in normal squamous epithelium and squamous cell carcinomas. These data suggest that IGFBP-3 is a target of transcriptional repression by Np63 and that this repression represents a mechanism by which tumors that overexpress p63 may be protected from apoptosis.

Key Words: p53 • squamous • carcinoma • repression

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